First Trials of Prontosil

While Domagk and his laboratory were so engaged, a handful of German doctors were quietly conducting the first clinical trials of Prontosil. In early 1933, selected physicians received from I.G. Farben samples of the compound under the label Streptozon or D4145. Patients suffering from streptococcal, staphylococcal, and other bacterial infections began to receive treatment with Streptozon almost immediately. Apart from mention of a single case at a medical society meeting in May 1933, however, no clinical results were published until February 1935. In that month, three clinical reports appeared in the same issue and immediately following Domagk's first publication on Prontosil in the Deutsche medizinische Wochenschrift. A fourth paper, also reporting results of clinical tests begun in 1933, appeared in the same journal in October 1935. Scrutiny of these reports permits evaluation of Hare's claim that clinical tests of Prontosil had been largely completed in 1933.33

One of the first physicians to receive Prontosil was Philipp Klee, who headed the medical clinic at nearby Wuppertal Hospital and was also a professor at Munich. Klee and his assistant, a young physician named Herbert Römer, had used Prontosil in treatment of an unspecified but apparently substantial number of cases of streptococcal infection between early 1933 and February 1935. In "numerous preliminary trials," they found Prontosil to be harmless and well tolerated. In one of these, a case of septic miscarriage that occurred not in the clinic but in Klee's private practice, the cessation of fever and recovery had been so rapid and striking as to propel them into sustained testing of the medicine. Unfortunately, this success had not been repeated in serious septic infections of the uterus, they reported, and, "as expected," Prontosil had not worked in cases of advanced septicemia. Undeterred, Klee and Römer had used Prontosil in treatment of streptococcal sore throats, tonsillar abscesses, tonsillar thrombophlebitis and lymphedenitis, jugular vein thrombosis, septic perimetritis, erysipelas, acute and ulcerative endocarditis, sepsis lenta, and acute and chronic polyarthritis. Confirmed cases of endocarditis lenta (inflammation of the interior lining of the heart) proved resistant to Prontosil. In contrast, Klee and Römer reported excellent results in treatment of septic sore throat and some of its most serious complications. In the past two years, they said, they had had no deaths from these conditions, a notable departure from previous experience. They did not feel that the precise role of Prontosil in treatment of septic sore throat and its complications was yet established, and urged physicians to attend carefully to the particulars of each case and not to neglect more conventional therapeutic measures. They did feel confident enough to recommend immediate use of Prontosil whenever the clinical picture suggested septic complications of sore throat.34

Klee and Römer gave details of three of their cases by way of example. One of these was offered as evidence that Prontosil also worked well in older patients:

62 year old engineer. Already in 1929 had severe thrombosis in leg after tibial fracture. Pain in swallowing and chills for 5 days. Temperature between 39 and 40 degrees. Gradually increasing difficulty of speech. In the last days pain in the neck on both sides over the jugular, then from today reddening and swelling. Hospitalization because of suspicion of jugular vein thrombosis. Threatening clinical picture. Confused. Dry tongue. Mucous membrane and throat edematous. Palatine arch in both sides arched outward and swollen. Entry to the throat narrowed. Tonsils not visible. Slight lockjaw. Speech barely understandable. On the neck and over the jugulars on both sides a slight edematous swelling with very great sensitivity to pressure. Over the left jugular hand-sized redness and edema. Treatment 2 times a day with 10 cc., later once a day with 10 cc. Prontosil intravenously and 3 times a day 0.6 g. by mouth. Already on the third day considerable improvement, gradual decline of the swelling and fever, after a further 9 days completely free of fever, after a further 14 days free of complaints and discharged cured.35

Success came also with use of Prontosil in cases of erysipelas of the face and head. A streptococcal infection of the skin and subcutaneous tissue, erysipelas is characterized by a spreading inflammation and redness in the affected areas. "The critical cessation of fever in erysipelas cases and the rapid restoration of skin processes was in some cases so striking," Klee and Römer reported, "that we could scarcely doubt a connection with the therapy, although the judgment in erysipelas is, as is known, always especially difficult." Less certain was the effect of Pron-tosil on polyarthritic disorders, where the picture was clouded by use of Prontosil in combination with other modes of therapy. Uncertainty also surrounded the mode of administration. Klee and Römer believed that Prontosil was well absorbed in the intestine but had also found that better results often came from giving a much smaller dose intravenously, a procedure they recommended in all serious cases.36

Klee and Römer reported that Prontosil was "harmless, free of undesirable side effects, easily tolerated, and effective" and recommended its use especially in serious forms of streptococcal sore throat and its complications, and in erysipelas. Although they remained uncertain as to why intravenous administration was more effective, they had found that a suitable dosage was 10-20 cc of the 0.25 percent solution once or twice a day intravenously and 0.3-0.6 g. three times a day orally. They concluded that "we see in the use of the azo compound Prontosil an enrichment of our therapy."37

Similar good results were reported by H.T. Schreus, director of the Düsseldorf Medical Academy's Dermatological Clinic. In March 1933, Schreus and his assistant, Richard Foerster, had in their care an infant one and one-half years old on the verge of death from staphylococcal septicemia. The child suffered from serious weight loss and elevated temperature, and the whole body was covered with abscesses. Several weeks of treatment with existing chemotherapies had been to no avail. In these desperate circumstances, the doctors began to give the infant 0.05 g of Prontosil by mouth twice a day. They observed no immediate change, but on the third day the child's temperature dropped from 40°C to 39°C in the morning, then suddenly to 37°C in the evening. Thereafter, the temperature fell gradually to normal, the abscesses softened and could be opened by incision, the skin improved, the child began to gain weight, and a fundamental change in the child's condition was evident. Schreus reported that "the success in this case made an exceedingly deep impression on those who participated."38

Deep impression or not, Schreus found that he could not replicate the dramatic results of the first case on other patients with staphylococcal infections. Nor could he get satisfactory results with use of Prontosil in gonorrhea, although in early 1935 he was still using Prontosil against both gonorrhea and staphylococcal infections. The real success came with erysipelas. The clinic treated an unspecified but large number of cases, mostly of facial erysipelas of various durations and severities. The standard measures before Prontosil included injection of the compounds Streptosan and Omnadin, and topical treatments. Most cases responded favorably in three to eight days, but some resulted in serious and even fatal complications. "Now, after the introduction of Prontosil treatment, a completely unmistakable change occurred," Schreus wrote enthusiastically. In one and one-half years of Prontosil treatment, the clinic had not had a single case of therapy-resistant erysipelas. "The rule is that already on the next day, at the latest on the second day after administration of two to six grams of Prontosil by mouth, the temperature drops to normal and the erysipelas is brought to a stop. We have seen this striking success in cases that were already treated elsewhere for a long time without results," he reported. Schreus was forthright in his conclusion, writing that "we have in Prontosil for the first time an agent that undoubtedly permits a causal treatment of erysipelas and indeed is to be spoken of as a true chemotherapeutic agent.. . [and] its specific action in erysipelas alone justifies its introduction into practice."39

Puerperal (childbed) fever, too, was apparently yielding to treatment with Prontosil. Eugen Anselm, an assistant in Max Henkel's University Women's Clinic in Jena, had received from I.G. Farben ampules of 10 cc and 20 cc of 0.25 percent Prontosil solution and also containers of 20 tablets of 0.3 g Prontosil each. With Domagk's animal trials in mind, he had used Prontosil as the exclusive therapy in two cases of bacteriologically confirmed streptococcal sepsis following miscarriage. Both patients were given intravenous doses of 20 cc Prontosil solution each day. In both cases, the temperature dropped after the first dose, and both patients were well and released after six doses, without evident side effects. Favorable results in what later proved to be mixed cases of streptococcal and staphy-lococcal infection led Anselm to conjecture that Prontosil not only exerted an elective action on streptococci but also had a general bactericidal action, or acted to mobilize the body's defenses including the reticuloendothelial system. On this basis, he tried Prontosil in those cases of confirmed mixed streptococcal and staphylococcal infection and purely staphylococcal infection, all with successful outcome. After such "unequivocal success," Anselm "henceforth as a matter of principle treated every case of puerperal fever immediately after admission exclusively with Prontosil without regard to the time-consuming and costly bacteriological confirmation of the infective agent." Thirteen cases treated successfully in this way led Anselm to give "the best recommendation of Prontosil for treatment of every form of pueperal fever."40

A more cautious but still positive evaluation of Prontosil in puerperal sepsis was published later in 1935 by Kurt Fuge, an assistant in L. Nurnberger's University Women's Clinic in Halle. The clinic had begun receiving Prontosil from I.G. Farben in 1933 and since then had treated 120 women for fever following birth or miscarriage, of whom fourteen were cases of sepsis, with very positive results. Given the background of skepticism in the medical community, however, Fuge felt it necessary to justify even making a trial of Prontosil. "In view of the fact that the chemotherapy of sepsis has enjoyed the unlimited and perhaps justified rejection of all authors who have had the opportunity of testing the results of all medicines recommended against sepsis," he admitted, "it may appear incomprehensible that we have nevertheless tried to improve the therapy of sepsis with this new medicine." Fuge held that past failures did not justify the rejection of new medicines on principle, and that they should be tried provided they did the patient no harm. In his view, the latter condition, which Prontosil satisfied, was critical since the body's powers of resistance had to be strengthened in every way possible: "the etiological treatment of sepsis [i.e., chemotherapy] is always only a support to this general treatment." All this said, he conceded that he was not as optimistic about Prontosil's prospects as some authors, and that his final judgment would have to await further clinical trials.41

The early German clinical trials of Prontosil fell into a clear pattern. Soon after filing its patent application on Prontosil, I.G. Farben began to release samples of the compound in liquid and tablet form to a handful of physicians, all of whom were on the staff of clinics independent of the company in which numbers of patients were treated for streptococcal and other bacterial infections. Clinical trials of Prontosil proceeded on a case-by-case basis at the discretion of individual physicians. Three of the four studies of Prontosil described above began with dramatic successes in one or two individual cases. These early successes appear to have played an important role in prompting continuation of the trials against a background of numerous previous failures of other drugs and some skepticism, a background sharply underlined by Fuge.

Investigating physicians typically gave close attention to the particulars of their cases, including the precise nature of the illness, the patient's tolerance of the medication, effective dosages, mode of administration, and failures. If patient consent to treatment with an experimental drug was asked for or obtained, the fact was nowhere recorded in any of these reports. None of the doctors mentioned large-scale or controlled clinical trials or appeared to be aware of their necessity or desirability. Lack of awareness of the utility of controls is all the more striking in view of the recurrent problems raised in the clinical trials. The physicians testing Prontosil confessed themselves unable to distinguish with certainty in all cases between the effects due to Prontosil and the ordinary variability in the course of untreated infections. Multiple therapies, including Prontosil, applied to the same case raised even more complex problems of interpretation. So, too, did cases of mixed infection, even where Prontosil was the sole therapy used.

Given these sources of confusion, the number of different kinds of strepto-coccal infections, not to mention staphylococcal or other types, on which the action of Prontosil had to be assessed, and the atmosphere of skepticism in which they worked, it is hardly surprising that physicians carrying out the first clinical trials of Prontosil remained tentative or uncertain on many points. Nor is it surprising that the preliminary trials occupied the greater part of two years, although that time exceeded by about a year the average laid down in the company's 1930 internal report for the clinical testing of a new compound. Hare's contention that many clinical trials were completed in 1933 and his conjecture that the company simply sat on the results for an additional year or more therefore appear implausible at best. More remarkable is that, in spite of limitations of methodology and the complexity of the phenomena under study, the physicians testing Prontosil were able to confidently recommend its use in erysipelas, puerperal fever, and the complications of streptococcal sore throat and that the company was prepared to act on these conclusions, advanced by a small number of clinicians on the basis of a small number of cases, by early 1935.42

This account is consistent with the position taken later by Domagk. Speaking in 1961 to the French Society of Chemotherapy and Serology, Domagk responded indignantly to characterizations of the delay between the first laboratory results in 1932 and the first publication in 1935 as "incomprehensible and mysterious" and underlined the need to confirm the clinical results so as not to raise false hopes among doctors and patients.43

Despite its initial plausibility, therefore, Hare's thesis is supported neither by the record of the laboratory development of Prontosil nor by that of its early clinical testing. Against Hare's views, finally, we must place several errors in his reasoning and a number of characteristics of the Elberfeld research endeavor that are misconstrued or not taken into account by his argument. Hare appears to have little sense of the background of chemotherapeutic research at Elberfeld. Thus, the significance of such predominant ideas as the principle of basic alkylation, the kind of analogical reasoning that made Atabrine a source of inspiration to Miet-zsch and Klarer, and the mystique of color referred to by Auhagen does not enter into his interpretation of the actions of Elberfeld researchers. At the same time, Hare imputes to these investigators questions and procedures of dubious relevance. So, for example, he supposes that the testing of intermediate products for therapeutic action was routine at Elberfeld, which does not appear to have been the case. Apparently determined to make recognition of sulfanilamide's therapeutic qualities appear inexorable, he misrepresents the significance of what he takes to be Walter Jacobs and Michael Heidelberger's 1919 finding in research at the Rockefeller Institute that a sulfonamide-containing azo-cinchona compound had antibacterial action in vitro. 44

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